Celldex Therapeutics initiates Phase 1/2 study in metastatic melanoma

Safety pilot and expansion study will examine the investigational combination of varlilumab and ipilimumab (Yervoy; Bristol-Myers Squibb) in patients with Stage III or IV metastatic melanoma

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HAMPTON, N.J.—Celldex Therapeutics, Inc. has announced the initiation of a Phase 1/2 safety pilot and expansion study examining the investigational combination of varlilumab and ipilimumab (Yervoy®; Bristol-Myers Squibb) in patients with Stage III or IV metastatic melanoma. Varlilumab is Celldex's fully human monoclonal antibody that targets CD27, a critical co-stimulatory molecule in the immune activation cascade. Ipilimumab, a recombinant, human monoclonal antibody that blocks CTLA-4, is FDA approved for the treatment of unresectable or metastatic melanoma. In the Phase 2 portion of the study, patients with tumors that express NY-ESO-1 will also receive CDX-1401, Celldex's off-the-shelf antibody-based dendritic cell vaccine that targets tumors expressing the NY-ESO-1 oncoprotein.  
The three agents in this study were specifically selected because they uniquely intervene at key points of immune regulation and because Celldex has observed enhanced activity in preclinical studies when varlilumab is combined with either checkpoint inhibitors or with vaccines. In addition, this study will also build on previous clinical data from the CDX-1401 experience that suggests that CDX-1401 may predispose patients to better outcomes on checkpoint inhibitors, including ipilimumab.
"We believe sophisticated combination approaches centered on immunotherapy hold significant promise for the treatment of cancer and, to this end, are committed to exploring novel combinations across a broad array of mechanisms and indications. This latest trial marks the third Phase 1/2 combination study that varlilumab has entered and the first three-drug combination study," Thomas Davis, M.D., executive vice president and chief medical officer of Celldex said in a statement.
The Phase 1 part of the study will assess the safety and tolerability of varlilumab at 0.3 and 3.0 mg/kg in combination with ipilimumab at 3 mg/kg administered every three weeks to identify a recommended dose for the Phase 2 portion of the study. The Phase 2 study will include two cohorts—one comprised of patients who are NY-ESO-1 positive and one comprised of patients who are NY-ESO-1 negative. Patients who are NY-ESO-1 positive will also receive CDX-1401 dosed at 1 mg (with poly-ICLC at 2 mg given as an adjuvant) every three weeks in addition to varlilumab and ipilimumab. In total, up to four doses of study treatment will be administered. The primary objective for both cohorts is objective response rate up to 24 weeks (ORR6) using standard, modified World Health Organization response criteria. Secondary objectives for the Phase 2 study include safety and tolerability, immunogenicity, pharmacokinetics and further assessment of anti-tumor activity across a broad range of endpoints.  
Varlilumab is a fully human monoclonal antibody that targets CD27, a critical molecule in the activation pathway of lymphocytes. CD27 can be effectively manipulated with activating antibodies to induce potent anti-tumor responses and may result in fewer toxicities due to its restricted expression and regulation. Varlilumab is a potent anti-CD27 agonist that induces activation and proliferation of human T cells when combined with T cell receptor stimulation. In lymphoid malignancies that express CD27 at high levels, varlilumab may have an additional mechanism of action through a direct anti-tumor effect. Varlilumab has completed a Phase 1 dose-escalation study, demonstrating potent immunologic activity consistent with its mechanism of action and anti-tumor activity in patients with advanced, refractory disease. No maximum tolerated dose was reached and minimal toxicities were observed. Celldex has initiated a broad development program for varlilumab to explore its role as an immune activator in combination with a number of complementary investigational and approved oncology drugs. Varlilumab is currently being studied in three Phase 1/2 combination studies and several additional combination studies will be initiated in 2015, the company says.  
CDX-1401 is a next-generation, off-the-shelf cancer vaccine designed to activate the patient's immune system against cancers that express the tumor marker, NY-ESO-1. CDX-1401 consists of a fully human monoclonal antibody with specificity for the dendritic cell receptor DEC-205 genetically linked to the NY-ESO-1 tumor antigen. Celldex has accessed NY-ESO-1 through a licensing agreement with the Ludwig Institute for Cancer Research. By selectively delivering the NY-ESO-1 antigen to dendritic cells in the body, CDX-1401 is intended to induce robust immune responses against the antigen-expressing cancer cells.
Celldex is developing targeted therapeutics to address devastating diseases for which available treatments are inadequate. The company’s pipeline is built from a proprietary portfolio of antibodies and immunomodulators used alone and in strategic combinations to create novel, disease-specific therapies that induce, enhance or suppress the body's immune response.

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